Certain benzoxepins and their pharmaceutical compositions and methods

ABSTRACT

Certain specific substituted 9-N-(1-azabicyclo[3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepins and their valuable use as 5-HT 3  antagonists having CNS and gastric prokinetic activity and void of any significant D 2  receptor binding properties are disclosed. Methods for their preparation also are described.

FIELD OF THE INVENTION

This invention is directed to certain specific novel chemical compoundsand their valuable use as pharmaceutical agents as 5-HT₃ antagonistshaving unique CNS, anti-emetic and gastric prokinetic activity void ofany significant D₂ receptor binding properties. This invention alsodescribes novel processes necessary for their preparation.

SUMMARY OF THE INVENTION

This invention relates to the compounds described by general Formula Iand to therapeutic compositions comprising as active ingredient acompound of Formula I: ##STR1## where:

X is hydrogen or halo;

Y is hydrogen, amino or loweralkylamino;

R₁ and R₂ are independently hydrogen or loweralkyl; and pharmaceuticallyacceptable salts thereof.

Preferred compounds of this invention include those where:

X is halo and Y, R₁ and R₂ are hydrogen;

Y is amino or loweralkylamino and X, R₁ and R₂ are hydrogen; and

X is halo, Y is amino and R₁ and R₂ are hydrogen.

More preferred compounds include those where halo is chloro or bromo andloweralkyl is methyl.

The present compounds may be prepared by the following generalprocedure: ##STR2##

Condensation of a substituted2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid, acid halide or esterwith 4-amino-1-azabicyclo[3.3.1]nonane results in the correspondingsubstituted benzoxepin-9-carboxamide. In general this reaction may becarried out at 0° C. by adding ethyl chloroformate to a reaction mixtureof the acid in chloroform in the presence of triethylamine. This is thenreacted with 4-amino-1-azabicyclo[3.3.1.]nonane to obtain the desiredproduct. Condensation may also be carried out in the presence of adehydrating catalyst such as a carbodiimide in a solvent at normaltemperatures.

The starting materials, that is the substituted2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acids are also novel. Theymay be prepared by the following reaction schemes. ##STR3## Whenα-tetralone(1) is treated with m-chloroperbenzoic acid the sevenmembered 1-benzoxepin-2-one(2) is formed. Treatment with lithiumaluminum hydride in a THF solution at 0° C. opens the ring to formo-hydroxypropylphenol(3). This in turn when treated with one equivalentof tosylchloride in the presence of triethylamine forms the primarytosylate which when treated with sodium hydride in THF ring closes toform 2,3,4,5-tetrahydro-1-benzoxepin(5). Treatment of the latter with amixture of n-butyl lithium and tetramethylethylenediamine results in the9-lithio compound which is then carboxylated with dry ice to form the2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid(6), upon acidicworkup.

When R₁ and R₂ substitution is desired, the following reactions may becarried out. ##STR4##

When 1-benzoxepin-2-one(2) is treated with an excess of Grignard reagentand acidified, the ring opened diol results. Treatment with tosic acidat raised temperatures gives the 2,2-disubstituted-1-benzoxepin(8) whichagain upon treatment with n-butyl lithium and tetramethylethylenediamineand carbon dioxide as above gives the2,3,4,5-tetrahydro-2,2-disubstituted-1-benzoxepin-9-carboxylic acid (9).When a controlled amount of Grignard reagent is used the resultant ringopened product is the 2-pentanone compound(10). Reduction with lithiumaluminum hydride results in the diol(11). This is then treated as aboveto obtain 2,3,4,5-tetrahydro-2-substituted-1-benzoxepin-9-carboxylicacid(12). ##STR5##

When the 9-carboxylic acids 6, 9 and 12 are treated withN-chlorosuccinimide or N-bromosuccinimide in a polar medium (DMF) atroom temperature, the resulting halogenated products 13, and 15 areformed. ##STR6## where X is chloro or bromo.

When it is desirable to have an amine or alkylamine function in the6-position of the 1-benzoxepin ring, then the following reactionsynthesis may be formed. ##STR7## where R is hydrogen or loweralkyl.

4-Aminosalicyclic acid is esterified with methanol and HCl followed byacylation of the amine with acetyl chloride/pyridine. The resultingphenol is then O-alkylated with allylbromide under basic conditions in apolar medium to obtain the allylphenyl ether(16). Claisen rearrangementat high temperature results in the methyl3-allyl-4-acetylaminosalicylates(17). Treatment of the latter withchloromethyl methyl ether in methylene chloride in the presence ofpotassium t-butoxide gives the O-methoxymethylethers(18). The allylderivatives(18) are next converted to the aldehydes(19) using sodiumperiodate and catalytic osmium tetroxide. Treatment of the resultingaldehyde(19) with 2-tetrahydropyranyloxyethyl triphenylphosphoniumbromide/BuLi results in formation of the olefin(20) upon hydrolysis ofthe methoxymethyl and tetrahydropyranyl ethers. Following catalytichydrogenation of the double bond, tosylation of the primary alcohol andcyclization with sodium hydride the methyl6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylates result. Thelatter may be hydrolyzed and deacetylated with aqueous base (such as 10%sodium hydroxide) in polar solvent at raised temperatures to obtain thedesired 6-amino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid(23).The above sequence of reactions may also be carried out on4-loweralkylamino salicylic acid to obtain6-loweralkylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid.

Treatment of methyl6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate withN-chlorosuccinimide or N-bromosuccinimide results in halogenation at the7-position(24). When compound 24 is treated with base as abovehydrolysis gives6-amino-7-halo-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid(25).

When R₁ is methyl and R₂ is hydrogen then the above reactions may befollowed using 2-tetrahydropyranyloxypropyl triphenylphosphonium bromidein place of 2-tetrahydropyranyloxyethyl triphenylphosphonium bromide inreaction with the 2-methoxymethyloxy-3-carbomethoxy-6-acetylaminophenylacetaldehyde(19). This results in2-methyl-6-amino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid and2-methyl-6-amino-7-halo-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylicacid. ##STR8##

Again, it is understood that when it is desired that Y isloweralkylamino, then the above sequence of reactions are carried outwith the proper amine.

When R₁ and R₂ are both substituted such as with methyl groups (35,37),then the Wittig reagent used is ##STR9## in place of ##STR10## in theforegoing reaction sequence. Ring closure after reduction is carried outas before with p-tosic acid at raised temperatures. ##STR11##

When it is desired that Y is loweralkylamino it is also convenient todeacetylate the 6-acetylamino-9-carbomethoxy compound with sodiummethoxide and then react the amine with an alkyliodide to form thealkylamino compound in the usual manner. The ester may then behydrolyzed with sodium hydroxide as before. ##STR12##

The compound of this invention have at least one asymmetric carbon atomand may have two centers when R₁ ≠R₂. As a result, the compounds ofFormula I may be obtained either as racemic mixtures or as individualenantiomers. When two asymmetric centers are present the product mayexist as a mixture of two diasteromers. The product may be synthesizedas a mixture of the isomers and then the desired isomer separated byconventional techniques such as chromatography or fractionalcrystallization from which each diasteromer may be resolved. On theother hand, synthesis may be carried out by known sterospecificprocesses using the desired form of the intermediate which would resultin obtaining the desired specificity.

It is convenient to carry out condensation of the substituted2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid with4-amino-1-azabicyclo[3.3.1.]nonane using the sterospecific materials.Thus, the 2-substituted-1-benzoxepin-9-carboxylic acid is resolved priorto condensation with resolved 4-amino-1-azabicyclo[3.3.1.]nonane.

The compounds of this invention may be readily converted to theirnon-toxic acid addition salts by customary methods in the art. Thenon-toxic salts of this invention are those salts the acid component ofwhich is pharmacologically acceptable in the intended dosages, includingthose prepared from inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, andfrom organic acids such as methane sulfonic acid, benzenesulfonic acid,acetic acid, propionic acid, malic acid, oxalic acid, succinic acid,glycolic acid, lactic acid, salicyclic acid, benzoic acid, nicotinicacid, phthalic acid, stearic acid, oleic acid, abietic acid, etc.

We have found that the compounds of this invention have gastricprokinetic, anti-emetic and lack D₂ receptor binding activity and assuch possess therapeutic value in the treatment of upper bowel motilityand gastroesophageal reflux disorders. Further, the compounds of thisinvention may be useful in the treatment of disorders related toimpaired gastrointestinal motility such as retarded gastric emptying,dyspepsia, flatulence, oesophageal reflux, peptic ulcer and emesis. Thecompounds of this invention exhibit 5-HT₃ antagonism and are consideredto be useful in the treatment of psychotic disorders such asschizophrenia and anxiety and in the prophylaxis treatment of migraineand cluster headaches. We have further found that these compounds areselective in that they have little or no dopaminergic antagonistactivity.

Various tests in animals can be carried out to show the ability of thecompounds of this invention to exhibit pharmacological responses thatcan be correlated with activity in humans. These tests involve suchfactors as the effect of the compounds of Formula I on gastric motility,emesis, selective antagonism of 5-HT₃ receptors and their D2 dopaminereceptor binding properties.

It has been found that the compounds of this invention when tested inthe above variety of situations show a marked activity.

One such test is the "Rat Gastric Emptying: Amberlite Bead Method". Thistest is carried out as follows:

The study is designed to assess the effects of a test agent on gastricemptying of a solid meal in the rat. The procedure is a modification ofthose used in L. E. Borella and W. Lippmann (1980) Digestion 20: 26-49.

Procedure

Amberlite® beads are placed in a phenol red solution and allowed to soakfor several hours. Phenol red serves as an indicator, changing the beadsfrom yellow to purple as their environment becomes more basic. Aftersoaking, the beads are rinsed with 0.1 NaOH to make them purple and thenwashed with deionized water to wash away the NaOH.

The beads are filtered several times through 1.18 and 1.4 mm sieves toobtain beads with diameters in between these sizes. This is done usinglarge quantities of deionized water. The beads are stored in salineuntil ready to use.

Male Sprague-Dawley rats are fasted 24 hours prior to the study withwater ad libitum. Rats are randomly divided in treatment groups with anN of 6 or 7.

Test agents are prepared in 0.5% methylcellulose and administered to therats orally in a 10 ml/kg dose volume. Control rats receive 0.5%methylcellulose, 10 ml/kg p.o. One hour after dosing, rats are given 60Amberlite® beads intragastrically. The beads are delivered via a 3 inchpiece of PE 205 tubing attached to a 16 gauge tubing adapter andsyringe. A small piece of PE 50 tubing is placed inside the tubingadapter to prevent the beads from being pulled back into the syringe.The beads are flushed into each rat's stomach with 1 ml saline.

Rats are sacrificed 30 minutes after receiving the beads and theirstomachs are removed. The number of beads remaining in each stomach iscounted after rinsing the beads with NaOH.

The number of beads remaining in each stomach is subtracted from 60 toobtain the number of beads emptied. The mean number of beads±S.E.M. isdetermined for each treatment group. The percent change from control iscalculated as follows: ##EQU1##

Statistical significance may be determined using a t-test forindependent samples with a probability of 0.05 or less considered to besignificant.

In order to demonstrate the ablity of the compounds of this invention asanti-emetic agents the following test for "Cisplatin-Induced Emesis inthe Ferret" may be used. This test is a modified version of a paperreported by A. P. Florezyk, J. E. Schurig and W. T. Brodner in CancerTreatment Reports: Vol 66, No. 1. January 1982.

Cisplatin had been shown to cause emesis in the dog and cat. Florczyk,et al. have used the ferret to demonstrate the same effects.

Procedure

Male castrated, Fitch ferrets, weighing between 1.0 and 1.5 kg have anin Indwelling catheter placed in the jagular vein. After a 2-3 dayrecovery period, the experimental procedure is begun.

30 minutes prior to administration of cisplatin, ferrets are dosed withthe compound in 0.9% saline (i.v.) at a dose volume of 2.0 ml/kg.

45 minutes after administration of cisplatin, ferrets are again dosedwith the 0.9% saline (i.v.) mixture at a dose volume of 2.0 ml/kg.

Cisplatin is administered (i.v.) 30 minutes after the first dosing withthe 0.9% saline. Cisplatin, 10 mg/kg is administered in a dose volume of2.0 ml/kg.

The time of cisplatin administration is taken as time zero. Ferrets areobserved for the duration of the experiment (4 hours). The elapsed timeto the first emetic episode is noted and recorded, as are the totalnumber of periods of emesis. PG,19

An emetic (vomiting) episode is characterized by agitated behavior, suchas pacing around the cage and rapid to and fro movements. Concurrentwith this behavior are several retching movements in a row, followed bya single, large, retch which may or may not expulse gastric contents.Immediately following the single large retch, the ferret relaxes. Singlecoughs or retches are not counted as vomiting episodes.

D-2 Dopamine Receptor Binding Assay

The D-2 dopamine receptor binding assay has been developed with slightmodifications using the method of Ian Cresse, Robert Schneider andSolomon H. Snyder, Europ. J. Pharmacol. 46: 377-381(1977). Spiroperidolis a butyrophenone neuroleptic whose affinity for dopamine receptors inbrain tissue is greater than that of any other known drug. It is ahighly specific D-1 dopamine (non-cyclase linked) receptor agent with K₁values of 0.1-0.5 for D-2 inhibition and 300 nM for D-1 inhibition.

Sodium ions are important regulators of dopamin receptors. The affinityof the D-2 receptor is markedly enhanced by the presence of millimolarconcentrations of sodium chloride. The Kd in the absence and presence of120 mM sodium chloride is 1.2 and 0.086 nM respectively. Sodium chloride(120 mM) is included in all assays as a standard condition.

The caudate nucleus (corpus striatum) is used as the receptor sourcebecause it contains the highest density of dopamine receptors in thebrain and periphery.

Procedure

Male Charles-River rates weighing 250-300 g are decapitated and theirbrains removed, cooled on ice, and caudate dissected immediately andfrozen on dry ice. Tissue can be stored indefinitely at -70° C. Forassay caudate is homogenized in 30 ml of tris buffer (pH 7.7 at 25° C.)using the polytron homogenizer. The homogenate is centrifuged at 40,000g (18,000-19,000 RPM in SS-34 rotor) for 15 minutes. Pellet isresuspended in fresh buffer and centrifuged again. The final pellet isresuspended in 150 volumes of assay buffer.

Specific ³ H-spiroperidol binding is assayed in a total 2 ml reactionvolume consisting of 500 μl of caudate homogenate, 50 mM tris buffer (pH7.4 at 35° C.), 5 mM MgSO₄, 2 mM EDTA·2NA, 120 mM NaCl, 0.1% ascorbicacid, 0.4 nM ³ H-spiroperidol and test compound or assay buffer. Whencatecholamines are included in the assay, 10 μM pargyline should beincluded in the reaction mixture to inhibit monoamine oxidase. Samplesare incubated at 37° C. for 30 minutes followed by addition of 5 ml icecold 50 mM TRIS (pH 7.7 at 25° C.) and filtration through GF/B glassfiber filters on a Brandel Receptor Binding Filtration apparatus.Filters are washed twice with an additional 5 ml of tris buffer each.Assay groups are performed in triplicate and 1 μM d(+) butaclamol isused to determine nonspecific binding. Filters are placed in vialscontaining 10 ml of Ecoscint phosphor, shaken for 30 minutes and dpmdetermined by liquid scintillation spectrophotometry using a quenchcurve. Proteins are determined by the method of Bradford, M. Anal.Biochem 72, 248(1976) using BioRad's Rad's coomassie blue G-250 dyereagent. Bovine gamma globulin supplied by BIO-RAD is used as theprotein standard.

Bezold-Jarisch effect in anaesthetized rats

Male rats 260-290 g are anaesthetized with urethane 1.25 g/kg⁻¹ i.p.,and the trachea cannulated. The jugular vein is cannulated forintravenous (i.v.) injection of drugs. Blood pressure is recorded from acannula in the left carotid artery and connected to ahaparin/salinefilled pressure transducer. Continuous heart ratemeasurements are taken from the blood pressure recordings. TheBezold-Jarisch effect is evoked by rapid, bolus i.v. injections of 5-HTand measurements are made of the fall in heart rate. In each rate,consistent responses are first established with the minimum dose of 5-HTthat evokes a clear fall in heart rate. Injections of 5-HT are givenevery 12 minutes and a dose-response curve for the test compound isestablished by injecting increasing doses of compound 5 minutes beforeeach injection of 5-HT. The effect of the compound on the 5-HT-evokedbradycardia is calculated as a percent of the bradycardia evoked by 5-HTbefore injection of compound.

In separate experiments to measure the duration of 5-HT antagonismcaused by the compounds of this invention, a single dose of compound isinjected 5 minutes before 5-HT, and the effects of 7 repeated challengeswith 5-HT are then monitored. The effects of the compound on theefferent vagal limb of the Bezold-Jarisch reflex are checked byelectrically stimulating the peripheral end of a cut vagus nerve.Unipolar electrical stimulation is applied every 5 minutes via a pair ofsilver electrodes, using 1 ms rectangular pulses in 5 s trains with amaximally-effective voltage (20 V at 10 Hz). Pulse frequency may varyfrom 5-30 Hz and frequency-response curves are constructed before and 10minutes after i.v. injection of a single dose of compound.

The results of these above tests indicate that the compounds for thisinvention exhibit a valuable balance between the peripheral and centralaction of the nervous system and may be useful in the treatment ofdisorders related to impaired gastro-intestinal motility such as gastricemptying, dyspepsia, flatulence, esphogal reflux and peptic ulcer and inthe treatment of disorders of the central nervous system such aspsychosis.

The compounds of the present invention can be administered to amammalian host in a variety of forms adapted to the chosen route ofadministration, i.e., orally, or parenterally. Parenteral administrationin this respect includes administration by the following routes:intravenous, intramuscular, subcutaneous, intraocular, intrasynovial,transepthelially including transdermal, opthalmic, sublingual andbuccal; topically including opthalmic, dermal, ocular, rectal and nasalinhalation via insufflation and aerosol and rectal systemic.

The active compound may be orally administered, for example, with aninert diluent or with an assimilable edible carrier, or it may beenclosed in hard or soft shell gelatin capsules, or it may be compressedinto tablets, or it may be incorporated directly with the food of thediet. For oral therapeutic administration, the active compound may beincorporated with excipient and used in the form of ingestibel tablets,buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers,and the like. Such compositions and preprations should contain at least0.1% of active compound. The percentage of the compositions andpreparations may, of course, be varied and may conveniently be betweenabout 2 to about 6% of the weight of the unit. The amount of activecompound in such therapeutically useful compositions is such that asuitable dosage will be obtained. Preferred compositions or preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between about 50 and 300 mg of active compound.

The tablets, troches, pills, capsules and the like may also contain thefollowing: A binder such as gum tragacanth, acacia, corn starch orgelating; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, patato starch, lginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier. Various other materials may be present ascoatings or to otherwise modify the physical form of the dosage unit.For instance, tablets, pills, or capsules may be coated with shellac,sugar or both. A syrup or elixir may contain the active compound.sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and flavoring such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage unit form should bepharmaceutically pure and substantially non-toxic in the amountsemployed. In addition, the active compound may be incorporated intosustained-release preparations and formulations.

The active compound may also be administered parenterally orintraperiotoneally. Solutions of the active compound as a free base orpharmacologically acceptable salt can be prepared in water suitablymixed with a surfactant such as hydroxypropylcellulose. Dispersion canalso be prepared in glycerol, liquid polyethylene glycols, and mixturesthereof and in oils. Under ordinary conditions of storage and use, thesepreparations contain a preservative to prevent the growth ofmicroorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases the form must be sterile and must be fluid tothe extent that easy syringability exists. It may be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyethylene glycol, and the like), suitable mixtures thereof,and vegetable oils. The proper fluidity can be maintained, for example,by the use of a coating such as lecithin, by the maintenance of therequired particle size in the case of dispersion and by the use ofsurfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimersal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars or sodium chloride. Prolonged absorption ofthe injectable compositions of agent delaying absorption, for example,aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredient into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vaccum drying and the freeze dryingtechnique which yield a powder of the active ingredient plus anyadditional desired ingredient from previously sterile-filtered solutionthereof.

The therapeutic compounds of this invention may be administered to amammal alone or in combination with pharmaceutically acceptablecarriers, as noted above, the proportion of which is determined by thesolubility and chemical nature of the compound, chosen route ofadministration and standard pharmaceutical practice.

The physician will determine the dosage of the present therapeuticagents which will be most suitable for prophylaxis or treatment and willvary with the form of administration and the particular compound chosen,and also, it will vary with the particular patient under treatment. Hewill generally wish to initiate treatment with small dosages by smallincrements until the optimum effect under the circumstances is reached.The therapeutic dosage will generally be from 0.1 to 20 mg or from about0.01 mg to about 50 mg/kg of body weight per day and higher although itmay be administered in several different dosage units from once toseveral times a day. Higher dosages are required for oraladministration.

The compounds of this invention may be prepared by the followingrepresentative examples.

EXAMPLE 1 1-Benzoxepin-2-one

To 100 g of m-chloroperbenzoic acid in 1 l of chloroform at 0° C. isadded dropwise 100 g of α-tetralone in 250 ml chloroform. After 5 daysof stirring at room temperature the reaction mixture is treatedcarefully with 1 l sat. NaHCO₃ and stirred for 1/2 hour. The organiclayer is separated, washed with 500 ml of water and solid NaHCO₃ untilno evolution of gas. The organic layer is separated washed with sat.NaHCO₃ and water and dried (MgSO₄) After filtering and concentrating todryness it is vaccum distilled to obtain low melting material which isused directly in the next step.

EXAMPLE 2 3-(o-Hydroxyphenyl)-1-propanol

To 20 g of lithium aluminum hydride in 200 ml of THF at 0° C. is addeddropwise 84 g of 1-benzoxepin-2-one in 200 ml of THF. After addition iscomplete the reaction mixture is allowed to come to room temperature andstirred 11/4 hours. The reaction mixture is then chilled to 0° C. and 20ml water, 20 ml 15% of NaOH and 60 ml H₂ O are sequentially added. Themixture is then diluted with ethyl acetate, acidified and filteredthrough celite. The EtOAc layer is separated, dried (MgSO₄) andconcentrated to obtain 3-(-o-hydroxyphenyl)-1-propanol as a brown oilwhich is used directly in the next step.

EXAMPLE 3 3-(o-Hydroxyphenyl)-1-tosyloxypropane

To 79.2 g of the diol from Example 2 in 400 ml of methylene chloride isadded 100 ml of tiethylamine, followed by 91 g of tosyl chloride in 200ml methylene chloride. The reaction mixture is stirred at roomtemperature overnight. The salts are then filtered off and the mixturewashed with water, brine and water. The organic layer is dried (MgSO₄),filtered and concentrated to obtain3-(o-hydroxyphenyl)-1-tosyloxypropane as a light brown oil which is useddirectly in the next step.

EXAMPLE 4 2,3,4,5-Tetrahydro-1-benzoxepin

To a mixture of 18.22 g of sodium hydride (60% dispersed in mineral oil)and 200 ml THF is added dropwise at 0° C. a solution of 146 g ofo-tosyloxyphenol in 100 ml of THF. The reaction mixture is allowed tocome to room temperature overnight. The reaction mixture is then chilledand 20 ml of H₂ O is added slowly. The mixture is then diluted withethyl acetate and with brine and water. The organic layer is dried(MgSO₄), filtered, and concentrated purification by flash columnchromatography affords 2,3,4,5-tetrahydro-1-benzoxepin.

EXAMPLE 5 2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid

To 17.6 ml n-butyllithium (2.5M, 0.044 mol) in 63 ml hexane is addeddropwise (0.044 mol) 5.1 g tetramethylethylenediamine (TMEDA) and 5 g(0.034 mol) of 2,3,4,5-tetrahydro-1-benzoxepin. The reaction mixture isstirred overnight. The reaction mixture is then chilled to 0° C. andcarbonated with dry ice for an hour. Water (110 ml) is added and themixture is filtered and the aqueous phase acidified with 4N HCl. Theresultant oil is extracted into methylene chloride and dried (MgSO₄).After filtering and concentrating in vacuo,2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid results as a tansolid.

EXAMPLE 69-N-(1-Azabicyclo[3.3.1.]nonan-4-yl)-carboxamido-2,3,4,5-tetrahydro-1-benzoxepin

To an aqueous sodium hydroxide solution of 1.08 g (5.12 mmol) of4-amino-1-azabicyclo[3.3.1.]nonane dihydrochloride (0.2 g 50% NaOH(0.124 mmol of NaOH solution), is added 6 ml of pyridine and 1.0 g (5.21mol) of 2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid. To theresulting mixture is added 1.1 g (5.33 mmol) ofN,N'-dicyclohexylcarbodiimide (DCC). This is allowed to stir overnightat room temperature. To this is added an additional 0.2 g of DCC andstirring continued for 2 days. The reaction mixture is filtered, washedwith water and the filtrate heated (50° C.) under vaccum to remove theremaining pyridine. Water is added and the reaction mixture againreduced to dryness under vaccum. The residue is treated with dilute NaOHsolution to pH=12. The solution is extracted with methylene chloride.The combined organic layers are then dried (MgSO₄) filtered andconcentrated to obtain crude9-N-(1-azabicyclo[3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro1-benzoxepinwhich is purified by column chromotagraphy (5:5 methylenechloride/methanol).

EXAMPLE 7 7-Chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid

To a solution of 1.7 g (8.9 mmol) of2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid in 5 ml of DMF isadded 1.41 g(10.6 mmol) of N-chlorosuccinimide (NCS) in one portion atroom temperature. The solution is stirred overnight and then dilutedwith ethyl acetate and washed with water. The organic layer is thendried (MgSO₄), filtered and concentrated to obtain7-chloro-2,3,4,5-tetrahydro-1-enzoxepin-9-carboxylic acid.

EXAMPLE 87-Chloro-9-N-(1-azabicyclo[3.321.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepin

To a solution of 100 mg (0.4 mmol) of7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid in 3 mlchloroform is added 0.073 ml (52 mmol) of triethylamine in one portionat room temperature. The solution is cooled to 0° C. and 0.042 ml (0.44mmol) of ethylchloroformate is added dropwise. Stirring is continued for1 hour at 0° C. 4-amino-1-azabicyclo[3.3.1.]nonane dihydrochloride 852mg (4 mmol) is dissolved in 3 ml of sat. aq. K₂ CO₃ and the resultingsolution cooled to 0° C. The cold aqueous solution is added in oneportion to the choloroform solution with vigorous stirring. The reactionmixture is allowed to come to room temperature and stirred overnight.The reaction mixture is diluted with water and extracted withchloroform. The combined organic extracts are dried (MgSO₄), filteredand concentrated. Flash chromatography (10% MeOH/CHCl₃) removes theimpurities to afford7-chloro-9-N-(1-azabicyclo[3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepin(M.P. 166°-167° C.).

EXAMPLE 9 5-(o-Hydroxyphenyl)-2-methyl-1-pentanol

To a solution of 5 g (31 mmol) of 1-benzoxepin-2-one in 50 ml of etheris added dropwise a solution of 62 mmol (2 eq) of methyl magnesiumbromide in ether at 0° C. After addition is completed the reactionmixture is stirred 1 hour at 0° C. and acidified slowly at 0° C. with 1NHCl (20 ml). The reaction mixture is then diluted with water andextracted with ether. The combined organic extracts are dried (MgSO₄),filtered and concentrated to obtain5-(o-hydroxyphenyl)-2-methyl-2-pentanol as a colorless oil which is useddirectly in the next step.

EXAMPLE 10 2,2-Dimethyl-2,3,4,5-tetrahydro-1-benzoxepin

To a solution of 100 mg (0.52 mmol)5-(o-hydroxyphenyl)-2-methyl-2-pentanol in 2 ml chloroform is added 25mg (25 wt %) of p-tosic acid in one portion. The resulting solution isthen heated at 80° C. for 2 hours. The reaction mixture is then dilutedwith methylene chloride and washed with a sat. solution of sodiumbicarbonate. The organic layer is dried (MgSO₄), filtered andconcentrated to obtain 2,2-dimethyl-2,3,4,5-tetrahydro-1-benzoxepinwhich is used directly in the next step.

EXAMPLE 11 2,2-Dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylicacid

To a solution of 23.18 mmol (1.2 eq) of n-butyl lithium (9.3 ml of 2.5Msolution in hexanes) is added or 3.45 ml (23.18 mmol) oftetramethylethylenediamine dropwise at room temperature. To thisresulting solution is added 3.4 g (19.32 mmol) of2,2-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin. After stirring for 18hours the reaction mixture is cooled to 0° C., 20 ml hexane added andgaseous CO₂ bubbled into the mixture for 1 hour. At this time sufficientwater is added to dissolve all the salts. The hexanes are then removedand the aqueous layer washed with hexane. The aqueous layer is acidifiedto about pH 2 with 3N HCl and extracted with methylene chloride. Thecombined organic extracts are dried (MgSO₄), filtered and concentratedto dryness to obtain2,2-dimethyl-2,3,4-5-tetrahydro-1-benzoxe-pin-9-carboxylic acid as acolorless oil.

EXAMPLE 122,2-Dimethyl-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid

To a solution of 3.6 g (16.4 mmol) of2,2-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid in 20 mlof DMF is added 2.6 g (19.7 mmol) of N-chlorosuccinimide in one portionat room temperature. The resulting solution is stirred for 31/2 days.The reaction mixture is then diluted with ethyl acetate washed withwater, and the organic layer is dried (MgSO₄), filtered and concentratedto obtain2,2-dimethyl-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid.

EXAMPLE 132,2-Dimethyl-7-chloro-9-N-(1-azabicyclo[3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepin

To a solution of 250 mg (1 mmol)2,2-dimethyl-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acidin 3 ml of chloroform is added 0.21 ml (1.5 mmol) of triethylamine inone portion at room temperature. The solution is cooled to 0° C. andethyl chloroformate is added dropwise. Stirring is continued for 1 hourat 0° C. A cold (ice bath) solution of4-amino-1-azabicyclo[3.3.1.]nonane dihydrochloride 2 g. (1 mmol) in 3 mlof sat. D₂ CO₃ is added in one portion and stirring continued at roomtemperature for 5 hours. The reaction mixture is diluted with water andextracted with chloroform. The combined organic extracts are dried(MgSo₄), filtered and concentrated. Flash chromatography (10%MeOH/CHCl₃) gives pure2,2-dimethyl-7-chloro-9-N-(1-azabicyclo[3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepinwhich is crystalized from MeOH/ether.

EXAMPLE 14

When Examples 9, 2, 10 and 11 are followed stepwise but 1 eq of Grignardreagent is used in Example 9 then the product obtained in Example 11 is2-methyl-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid.

EXAMPLE 15

Following the chorinating procedures of Example 12 but starting with2-methyl-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid in place of2,2-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid, theproduct obtained is2-methyl-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid.

EXAMPLE 16

When the procedure of Example 13 is followed but the carboxylic acidsprepared by Examples 11, 14 and 15 are used in place of2,2-dimethyl-7-chloro-2,3,4, 5-tetrahydro-1-benzoxepin-9-carboxylic acidthen the products prepared are:

2,2-dimethyl-9-N-(1-azabicyclo[3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepin

2-methyl-9-N-(1-azabicyclo[3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepinand2,2-methyl-7-chloro-9-N-(1-azabicyclo[3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepin

EXAMPLE 17 Methyl 4-aminosalicylate

To a solution of 25 g (118.5 mmol) of 4-aminosalicylic acid sodium saltin 250 ml of methanol is bubbled in anhydrous HCl gas at roomtemperature. Addition of HCl gas is continued for 30 minutes. Excessmethanol is removed in vacuo and the residue taken up in ethyl acetateand washed with saturated aqueous NaHCO . The organic layer is driedover MgSO₄, filtered and concentrated, giving methyl 4aminosalicylatewhich is used directly in the next step.

EXAMPLE 18 Methyl 4-acetylaminosalicylate

To a solution of 10 g (59.9 mmol) of methyl 4-aminosalicylate in 100 mlof CH₂ Cl₂ is added 6.8 ml (83.9 mmol) of pyridine in one portion atroom temperature. The solution is cooled to 0° C. and 4.7 ml (65.9 mmol)of acetyl chloride is added dropwise. After addition is complete thereaction mixture is let stand 30 minutes at room temperature. Thereaction mixture is diluted with water and extracted with CH₂ Cl₂. Thecombined organic extracts are dried over MgSO₄, filtered andconcentrated to provide methyl 4-acetylaminosalicylate which is useddirectly in the next step.

EXAMPLE 19 Methyl 2-allyloxy-4-acetylaminobenzoate

To a solution of 10 g (47.8 mmol) of methyl 4-acetylaminosalicylate in30 ml of DMF is added 19.8 g (143.4 mmol) of finely ground potassiumcarbonate in a single portion at room temperature, followed by 8.3 ml(95.6 mmol) of allyl bromide in a similar fashion. The reaction mixtureis heated to 60° C. and stirred at that temperature for 4 hours. Aftercooling to room temperature the reaction mixture is diluted with ethylacetate and washed with water. The organic layer is dried over MgSO₄,filtered and concentrated. Flash chromatography (10% ethylacetate/hexane) provides methyl 2-allyloxy-4-acetylaminobenzoate whichcan be used directly in the next step.

EXAMPLE 20 Methyl 3-allyl-4-acetylaminosalicylate

A solution of 5 g (20.1 mmol) of the allyl ether from Example 19 in 20ml of toluene is heated at 200° C. in a sealed tube for 24 hours. Aftercooling to room temperature a precipitate begins forming and thereaction mixture is cooled further to 0° C. The precipitate is filteredoff and allowed to air dry, giving methyl3-allyl-4-acetylaminosalicylate which can be used directly in the nextstep.

EXAMPLE 21 Methyl 2-methoxymethyloxy-3-allyl-4-acetylaminobenzoate

To a solution of 10 g (40.2 mmol) of methyl3-allyl-4-acetylaminosalicylate in 50 ml of CH₂ Cl₂ is added 7.9 ml(56.3 mmol) of triethylamine in one portion at room temperature,followed by 3.3 ml (44.2 mmol) of chloromethyl methyl ether dropwise atroom temperature. Stirring is continued for 24 hours at roomtemperature. The reaction mixture is diluted with ethyl acetate andwashed with water. The organic layer is dried over MgSO₄, filtered andconcentrated. Flash chromatography (10% EtOAc/hexanes) affords puremethyl 2-methoxymethyloxy-3-allyl-4-acetylaminobenzoate.

EXAMPLE 222-Methoxymethyloxy-3-carbomethoxy-6-acetylaminophenylacetaldehyde

A solution of 5 g (17.1 mmol) of methyl2-methoxymethyloxy-3-allyl-4-acetylaminobenzoate in 20 ml of 1,4-dioxaneis heated to 45° C. and 0.86 ml (6.86 mmol) of a 1M solution of osmiumtetroxide in t-butanol is added in a single portion. Stirring iscontinued 15 minutes at 45° C. 7.32 g (34.2 mmol) of sodium periodate isadded portionwise and stirring is continued 1 hour. Cyclohexane (1 ml)is added and stirring continued for 1 hour. The reaction mixture is thendiluted with CH₂ Cl₂ and washed with water. The organic layer is driedover MgSO₄, filtered and concentrated. Flash chromatography (10%EtOAc/hexanes) affords pure2-methoxymethyloxy-3-carbomethoxy-6-acetylaminophenylacetaldehyde whichis used directly in the next step.

EXAMPLE 23 Methyl 3-(4'-hydroxy-2'-butenyl)-4-acetylaminosalicylate

To a suspension of 9.18 g (20.4 mmol) of2-tetrahydropyranyloxyethyltriphenylphosphonium bromide in 50 ml ofether is added 7.48 ml (18.7 mmol BuLi) of a 2.5M solution of butyllithium in hexanes, dropwise at 0° C. After addition is completestirring is continued 30 minutes at 0° C. To the solution of the ylideis added a solution of 5 g (17.0 mmol) of the aldehyde from Example 22in 25 ml of ether dropwise at 0° C. After addition is complete thereaction mixture is allowed to come to room temperature and is stirred 6hours at room temperature. The reaction mixture is diluted with etherand washed with water. The organic layer is separated and allowed tostand in a refrigerator overnight. The triphenylphospine oxide isfiltered off and the ether is removed in vacuo. The residue is dissolvedin 25 ml of THF and 25 ml of 6N HCl is added in one portion at roomtemperature. Stirring is continued for 24 hours at room temperature. THFis removed in vacuo and ethyl acetate is added. The mixture is washedwith water, saturated aqueous NaHCO₃ and brine. The organic layer isdried over MgSO₄, filtered and concentrated. Flash chromatography (20%EtOAc/hexanes) affords methyl3-(4'-hydroxy-2'-butenyl)-4-acetylaminosalicylate which can be useddirectly in the next step.

When tetrahydropyranyloxyethyltriphenylphosphonium bromide of Example 23is replaced with tetrahydropyranyloxypropyltriphenylphosphonium bromidethen the product prepared is methyl3-(4-hydroxy-4'-methyl-2'-butenyl)-4-acetylaminosalicylate.

EXAMPLE 24 Methyl 3-(4'-hydroxybutyl)-4-acetylaminosalicylate

To a solution of 5 g (14.7 mmol) of the olefin from Example 23 in 20 mlof ethyl acetate is added 0.5 g of 10% palladium on carbon in a singleportion at room temperature. The reaction mixture is stirred under apositive pressure of hydrogen for 24 hours. The reaction mixture isfiltered through celite (washed with ethyl acetate) and concentrated togive methyl 3-(4'-hydroxybutyl)-4-acetylaminosalicylate.

When methyl 3-(4'-hydroxy-2'-butenyl)-4-acetylaminosalicylate in Example24 is replaced with methyl3-(4'-hydroxy-4'-methyl-2'-butenyl)-4-acetylaminosalicylate then theproduct prepared is methyl 3-(4'-hydroxypentyl)-4-acetylaminosalicylate.

EXAMPLE 25 Methyl 3-(4'-Tosyloxybutyl)-4-acetylaminosalicylate

To 1.58 g of methyl 3-(4'-tosyloxybutyl)-4-acetylaminosalicylate in 8 mlof methylene chloride is added 2 ml triethylamine. To this mixture isthen added 1.82 g of tosyl chloride in 4 ml methylene chloride andstirred at room temperature overnight. The salts are then filtered offand the mixture washed with water, brine and water and dried (MgSO₄)This is then filtered and concentrated to dryness to obtain methyl3-(4'-tosyloxybutyl)-4-acetylaminosalicylate which is used directly inthe next step.

When methyl 3-(4'-hydroxybutyl)-4-acetylminosalicylate in Example 25 isreplaced with methyl 3-(4'-hydroxypentyl)-4-acetylaminosalicylate thenthe product prepared is methyl3-(4'-tosyloxypentyl)-4-acetylaminosalicylate.

EXAMPLE 26 Methyl6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate

To a solution of 5 g (14.6 mmol) of methyl3-(4'-tosyloxybutyl)-4-acetylaminosalicylate in 50 ml of THF is added0.64 g (16.1 mmol) of sodium hydride (60% dispersion in mineral oil)portionwise at room temperature. After addition is complete stirring iscontinued 24 hours at room temperature. Water is added dropwise todecompose excess NaH. The reaction mixture is diluted with ethyl acetateand washed with water. The organic layer is dried over MgSO₄, filteredand concentrated. Flash chromatography (5% EtOAc/hexanes) providesmethyl 6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate.

When methyl 3-(4'-tosyloxybutyl)-4-acetylaminosalicylate in Example 25is replaced with 3-(4'-tosyloxypentyl)-4-acetylaminosalicylate then theproduct prepared is methyl2-methyl-6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate.

EXAMPLE 27 6-Amino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid

To a solution of 5 g (19.0 mmol) of methyl6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboylate in 10 ml ofmethanol is added 10 ml of a 10% aqueous sodium hydroxide solution in asingle portion at room temperature. The reaction mixture is heated toreflux and maintained at that temperature for 2 hours. After cooling,methanol is removed in vacuo and the residue is diluted with water. ThepH of the solution is adjusted to 7 with 1N HCl and the solution isextracted with CH₂ Cl₂. The combined organic extracts are dried overMgSO₄, filtered and concentrated. Flash chromatography (30%EtOAc/hexanes) gives6-amino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid.

When methyl 6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylateof Example 27 is replaced with methyl2-methyl-6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylatethen the product prepared is2-methyl-6-amino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid.

EXAMPLE 28

6-Amino-9-N-(1-azabicyclo3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepin

To a solution of 1.28 g (6.2 mmol) of6-amino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid in 8 ml ofpyridine at 0° C. is added 1.4 g (6.8 mmol) ofN,N'-dicyclohexylcarbodiimide in one portion. This is stirred at 0° C.for 1 hour and then 1.31 g (6.2 mmol) 4-amino-1-azabicyclo[3.3.1.]nonanedihydrochloride is added in one portion. The mixture is allowed to cometo room temperature and stirred overnight. To this is added 8 ml of 1NNaOH and after 30 minutes the reaction mixture is filtered. The filtrateis taken up in methylene chloride, washed with water, dried (MgSO₄),filtered and concentrated to dryness to obtain6-amino-9-N-(1-azabicyclo[3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepin.

When 6-amino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid ofExample 28 is replaced with2-methyl-6-amino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid thenthe product prepared is2-methyl-6-amino-9-N-(1-azabicyclo[3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepin.

EXAMPLE 29 Methyl6-acetylamino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate

To a solution of 5 g (19.0 mmol) of methyl6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate from Example26 in 10 ml DMF is added 3.0 g (22.8 mmol) of N-chlorosuccinimide in asingle portion at room temperature. The resulting solution is allowed tostir 24 hours at room temperature. The reaction mixture is diluted withethyl acetate and washed with water. The organic layer is dried overMgSO₄, filtered, concentrated and subjected to flash chromatography (20%EtOAc/hexanes) to yield methyl6-acetylamino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate.This is used in the next step.

When methyl 6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylateof Example 29 is replaced with methyl2-methyl-6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylatethen the product prepared is methyl2-methyl-6-acetylamino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate.

EXAMPLE 30 6-Amino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylicacid

To a solution of 5 g (16.8 mmol) of methyl6-acetylamino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate in10 ml of methanol is added 10 ml of a 10% aqueous sodium hydroxidesolution in a single portion at room temperature. The solution is heatedto reflux and maintained for 2 hours. After cooling, methanol is removedin vacuo and the residue is diluted with water. The pH of this solutionis adjusted to 7 with 1N HCl. The neutral solution is extracted with CH₂Cl₂ and the combined organic extracts are dried over MgSO₄, filtered andconcentrated. Flash chromatography (30% EtOAc/hexanes) provides6-amino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid.

When methyl6-acetylamino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate ofExample 30 is replaced by methyl2-methyl-6-acetylamino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-caroxylatethen the compound prepared is2-methyl-6-amino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylicacid.

EXAMPLE 316-Amino-7-chloro-9-N-(1-azabicyclo[3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepin

To a solution of 900 mg (3.72 mmol) of6-amino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid in4.8 ml of pyridine at 0° C. is added 900 mg (4.09 mmol) ofN,N'-dicyclohexylcarbodiimide in one portion. This is stirred at 0° C.for 1 hour and then 740 mg (3.72 mmol) of4-amino-1-azabicyclo[3.3.1.]nonane dihydrochloride is added in oneportion. The mixture is allowed to come to room temperature and stirredovernight. To this is added 4.8 ml of 1N NaOH and after 30 minutes thereaction mixture is filtered. The filtrate is taken up in methylenechloride, washed with water, dried (MgSO₄), filtered and concentrated todryness to obtain6-amino-7-chloro9-N-(1-azabicyclo]3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepin.

When 6-amino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acidof Example 31 is replaced with2-methyl-6-amino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylicacid then the product prepared is2-methyl-6-amino-7-chloro-9-N-(1-azabicyclo[3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepin.

EXAMPLE 32

When 2-tetrahydropyranylpropyltriphenylphosphonium bromide is used inplace of 2-tetrahydropyranylethyltriphenylphosphonium bromide in Example23 and when the succeeding examples 24, 25 and 26 are followed, theproduct obtained is2-methyl-6-amino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid.

EXAMPLE 33

When methyl2-methyl-6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylateprepared by Example 32 is used in Example 29 in place of methyl6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate, then theproduct prepared is methyl2-methyl-6-acetylamino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate.

EXAMPLE 34

When methyl2-methyl-6-acetylamino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylateis used in place of methyl6-acetylamino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate inExample 30, then the product prepared is2-methyl-6-amino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylicacid.

EXAMPLE 35

When2-methyl-6-amino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylicacid is used in Example 31 in place of6-amino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid, thenthe product prepared is2-methyl-6-amino-7-chloro-9-N-(1-azabicyclo[3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepin.

EXAMPLE 36 Methyl 3-(2'-methyl-2'-hydroxypentyl)-4-acetylaminosalicylate

To a suspension of 20.4 mmol of ##STR13## in 50 ml of ether is added 16ml (20 mmol BuLi) of a 2.5M solution of butyl lithium in hexanes,dropwise at 0° C. After addition is complete stirring is continued 30minutes at 0° C. To the solution of the ylide is added a solution of 5 g(17.0 mmol) of the aldehyde from Example 22 in 25 ml of ether dropwiseat 0° C. After addition is complete the reaction mixture is allowed tocome to room temperature and is stirred 6 hours at room temperature. Thereaction mixture is diluted with ether and washed with water. Theorganic layer is separated and allowed to stand in a refrigeratorovernight. The triphenylphospine oxide is filtered off and the ether isremoved in vacuo. The residue is dissolved in 25 ml of THF and 25 ml of6N HCl is added in one portion at room temperature. Stirring iscontinued for 24 hours at room temperature. THF is removed in vacuo andethyl acetate is added. The mixture is washed with water, saturatedaqueous NaHCO₃ and brine. The organic layer is dried over MgSO₄,filtered and concentrated. Flash chromatography (20% EtOAc/hexanes)affords methyl 3-(2'-methyl-2'-hydroxypentyl)-4-acetylaminosalicylate.

EXAMPLE 37 Methyl3-(2'-methyl-2'-tosyloxypentyl)-4-acetylaminosalicylate

To 4 g of the diol from Example 36 in 20 ml of methylene chloride isadded 5 ml of triethylamine and 4.55 g of tosyl chloride in 10 ml ofmethylene chloride. This is stirred at room temperature overnight,filtered, washed with water and dried (MgSO₄). This is then filtered andevaporated to dryness to obtain methyl3-(2'-methyl-2'-tosyloxypentyl)-4-acetylaminosalicylate.

EXAMPLE 38 Methyl2,2-dimethyl-6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate

To a mixture of 2.2 g sodium hydride (60%) and 20 ml THF is addeddropwise at 0° C. a solution of 15 g of methyl3-(2'-methyl-2'-tosyloxypentyl)-4-acetylaminosalicylate in 10 ml THF.This is allowed to come to room temperature over several hours, thenchilled and 2 ml H₂ O added slowly. This is then diluted with ethylacetate, the salts filtered off, washed with water and brine, dried andconcentrated to dryness to obtain methyl2,2-dimethyl-6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylatewhich is used directly in the next step.

EXAMPLE 392,2-Dimethyl-6-amino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid

To a solution of 5.5 g (19.0 mmol) of methyl2,2-dimethyl-6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylatein 10 ml of methanol is added 10 ml of a 10% aqueous sodium hydroxidesolution in a single portion at room temperature. The reaction mixtureis heated to reflux and maintained at that temperature for 2 hours.After cooling, methanol is removed in vacuo and the residue is dilutedwith water. The pH of the solution is adjusted to 7 with 1N HCl and thesolution is extracted with CH₂ Cl₂. The combined organic extracts aredried over MgSO₄, filtered and concentrated. Flash chromatography (30%EtOAc/hexanes) gives2,2-dimethyl-6-amino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid.

EXAMPLE 402,2-Dimethyl-6-amino-9-N-(1-azabicyclo[3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepin

To a solution of 1.45 g (6.2 mmol) of2,2-dimetyl-6-amino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid in8 ml of pyridine at 0° C. is added 1.4 g (6.8 mmol) ofN,N'-dicyclohexylcarbodiimide in one portion. This is stirred at 0° C.for 1 hour and then 1.31 g (6.2 mmol) 4-amino-1-azabicyclo[3.3.1.]nonaneis added in one portion. The mixture is allowed to come to roomtemperature and stirred overnight. To this is added 8 ml of 1N NaOH andafter 30 minutes the reaction mixture is filtered. The filtrate is takenup in methylene chloride, washed with water, dried (MgSO₄), filtered andconcentrated to dryness to obtain2,2-dimethyl-6-amino-9-N-(1-azabicyclo[3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepin.

EXAMPLE 41 Methyl2,2-dimethyl-6-acetylamino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate

To a solution of 5.5 g (19.0 mmol) of methyl2,2-dimethyl-6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylatefrom Example 37 in 10 ml DMF is added 3.0 g (22.8 mmol) ofN-chlorosuccinimide in a single portion at room temperature. Theresulting solution is allowed to stir 24 hours at room temperature. Thereaction mixture is diluted with ethyl acetate and washed with water.The organic layer is dried over MgSO₄, filtered, concentrated andsubjected to flash chromatography (20% EtOAc/hexanes) to yield methyl2,2-dimethyl-6-acetylamino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate.This is used directly in the next step.

EXAMPLE 422,2-Dimethyl-6-amino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylicacid

To a solution of 5.46 g (16.8 mmol) of methyl2,2-dimethyl-6-acetylamino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylatein 10 ml of methanol is added 10 ml of a 10% aqueous sodium hyroxidesolution in a single portion at room temperature. The solution is heatedto reflux and refluxing maintained for 2 hours. After cooling, methanolis removed in vacuo and the residue is diluted with water. The pH ofthis solution is adjusted to 7 with 1N HCl. The neutral solution isextracted with CH₂ Cl₂ and the combined organic extracts are dried overMgSO₄, filtered and concentrated. Flash chromatography (30%EtOAc/hexanes) provides2,2-dimethyl-6-amino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylicacid.

EXAMPLE 432,2-Dimethyl-6-amino-7-chloro-9-N-(1-azabicyclo[3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepin

To a solution of 1 g (3.72 mmol) of2,2-dimethyl-6-amino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylicacid in 4.8 ml of pyridine at 0° C. is added 900 mg (4.09 mmol) ofN,N'-dicyclohexylcarbodiimide in one portion. This is stirred at 0° C.for 1 hour and then 740 mg (3.72 mmol) of4-amino-1-azabicyclo[3.3.1.]nonane dihydrochloride is added in oneportion. The mixture is allowed to come to room temperature and stirredovernight. To this is added 4.8 ml of 1N NaOH and after 30 minutes thereaction mixture is filtered. The filtrate is taken up in methylenechloride, washed with water, dried (MgSO₄), filtered and concentrated todryness to obtain2,2-dimethyl-6-amino-7-chloro-9-N-(1-azabicyclo[3.3.1.]nonan-4-yl)-carboxamido-2,3,4,5-tetrahydro-1-benzoxepin.

EXAMPLE 44

When N-chlorosuccinimide of Examples 7, 12, 15, 29 and 41 is replaced byN-bromosuccinimide then the corresponding bromo compounds are obtained.

EXAMPLE 45

When methyl 4-aminosalicylate of Example 17 is replaced with methyl4-methylaminosalicylate then the corresponding methylamino product isobtained in Examples 17 through 44.

We claim:
 1. A compound of the formula: where: ##STR14## where X is hydrogen or halo;Y is hydrogen, amino or loweralkylamino; R₁ and R₂ are independently hydrogen or loweralkyl; and pharmaceutically acceptable salts thereof.
 2. A compound according to claim 1 whereX is halo and Y , R₁ and R₂ are hydrogen.
 3. A compound according to claim 1 whereY is amino or loweralkylamino and X, R₁ and R₂ are hydrogen.
 4. A compound according to claim 1 whereX is halo, Y is amino or loweralkylamino and R₁ and R₂ are hydrogen.
 5. A compound according to claim 2 whereX is chloro thus forming 7-chloro-9-N-(1-azabicyclo[3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepin.
 6. A compound according to claim 2 whereX is bromo thus forming 7-bromo-9-N-(1-azabicyclo[3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepin.
 7. A compound according to claim 3 whereY is amino thus forming 6-amino-9-N-(1-azabicyclo[3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepin.
 8. A compound according to claim 3 whereY is methylamino thus forming 6-methylamino-9-N-(1-azabicyclo[3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepin.
 9. A compound according to claim 4 whereX is chloro and Y is amino thus forming 6-amino-7-chloro-9-N-(1-azabicyclo[3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepin.
 10. A compound according to claim 4 whereX is bromo and Y is amino thus forming 6-amino-7-bromo-9-N-(1-azabicyclo[3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepin.
 11. A compound according to claim 1 whereX is hydrogen, Y is hydrogen and R₁ and R₂ are methyl thus forming 2,2-dimethyl-9-N-(1-azabicyclo[3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepin.
 12. A compound according to claim 1 whereX is chloro, Y is hydrogen and R₁ and R₂ are methyl thus forming 2,2-dimethyl-7-chloro-9-N-(1-azabicyclo[3.3.1.]nonan-4-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepin.
 13. A method for the treatment of gastric disorders in humans and mammals comprising administering thereto an effective amount of a compound of the formula according to claim
 1. 14. A method for the treatment of emesis in humans and mammals comprising administering thereto an effective amount of a compound of the formula according to claim
 1. 